Antithrombotic therapy after left atrial appendage closure

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Boris Schmidt and KR Julian Chun

Uncertainty exists about the optimal post-interventional antithrombotic drug regimen as well as treatment duration after left atrial appendage closure; Boris Schmidt and KR Julian Chun review different strategies. Schmidt spoke on the subject at Cardiostim/EHRA Europace (Nice, France, 18–21 June).

For patients with a high stroke risk and contraindications to long-term oral anticoagulation left atrial appendage closure (LAAC) may be considered as an alternative strategy for stroke prevention (Class IIb, level of evidence C)1. Initially, enthusiasm for this intervention was dampened due to a high incidence of peri-procedural complications 2. Today, the speed of a widespread adoption is rather slowed by regulatory issues (not yet approved in the USA and poorly reimbursed in many European countries) than by safety concerns, owing to the relatively steep learning curve associated with an improved procedural safety profile 3.

The ultimate interventional goal is the complete sealing of the LAA in order to eliminate the major source of cardiac emboli. At best, the mechanical obliteration should obviate the need for any antithrombotic medication thereby minimising the risk of bleeding. However, following the implant, clots may form on the device and preventive measures need to be applied until complete endothelialisation of the occluder has occurred.

Uncertainty exists about the optimal post-interventional drug regimen as well as treatment duration. In the following review article, different strategies will be presented and discussed.

 
Patients without contraindications to oral anticoagulation

Two major randomised clinical trials investigated the performance of LAAC using Watchman (Boston Scientific) compared to oral anticoagulation using a vitamin K antagonist (VKA): PROTECT AF and PREVAIL2,4. While the former trial proved LAAC being non-inferior to VKA treatment with regard to the prevention of stroke, transient ischaemic attack, systemic embolism and cardiovascular death, PREVAIL failed to meet the non-inferiority criteria. Despite numerically similar event rates (18 months event rate: 0.064 (LAAC) versus 0.0063 (oral anticoagulation)), the upper credibility interval crossed the pre-specified boundary. It is of note, that the event rate in the VKA group (0.70 per 100 patient years) was considerably lower than expected referring to recent large scale randomised drug trials such as ARISTOTLE, RELY or ROCKET-AF5–7.

In both studies, patients received a combination of oral anticoagulation using warfarin plus acetylsalicylic acid (ASA) 75mg for 45 days, followed by six months of dual platelet inhibition with clopidogrel 75mg and lifelong continuation of ASA 75mg/day.

At the end of 12 months 99.3% had stopped oral anticoagulation therapy in PREVAIL (92% at six months in PROTECT).

During echocardiographic evaluation at 45 days post-implant, 3.4% of all patients exhibited a thrombus on the device 8. In the same time, bleeding complications occurred in six patients in the first six weeks during oral anticoagulation and ASA therapy, translating into an estimated annual bleeding rate of 10.5%. In the following study period, when patients received dual platelet inhibition, three (0.6%) patients presented with bleedings (1.6% per year).

In summary, the above mentioned drug regimen appears to be feasible in patients eligible for oral anticoagulation but it is associated with a considerable number of bleeding events. 

Patients with contraindications to oral anticoagulation

Owing to the current atrial fibrillation guidelines, most of the LAAC interventions are currently performed in patients intolerant to oral anticoagulation. Stroke prophylaxis is particularly challenging and to date, no randomised clinical trials have been performed in this patient population. However, various observational studies were conducted and published.

Due to the relative contraindication to oral anticoagulation, patients in the PLAATO study were treated with dual platelet inhibition consisting of clopidogrel 75mg and ASA 325mg for four to six weeks after LAAC, followed by lifelong ASA therapy 9. During echocardiographic follow-up no thrombi were detected on the device at one and/or six months. Moreover, complete LAA sealing was noted in >98% of the patients.

A more recent study investigated the feasibility of dual platelet inhibition for six months after a Watchman implantation in patients intolerant to oral anticoagulation 10. The most common reason for oral anticoagulation intolerance was a history of bleeding in 93% of all patients. During follow-up, thrombus formation on the device was discovered in 6/150 patients (4%) most likely causing stroke in one patient. In the remaining cases, thrombi resolved after four to eight weeks of low-molecular weight heparin (LMWH) administration (one patient with spontaneous resolution).

During the first six months of follow-up, five patients experienced a bleeding complication translating in an estimated annual bleeding rate of 6.6%.

Additional data from observational studies report conflicting results with regard to the benefits of dual platelet inhibition instead of oral anticoagulation after LAAC.

Meincke and co-workers reported on 59 consecutive patients who underwent LAAC with Watchman 11. While patients eligible for oral anticoagulation (n=7) received antithrombotic treatment according to the PROTECT AF protocol, those with contraindications to oral anticoagulation received dual platelet inhibition for three to six months depending on the bleeding risk (n=52). On-device thrombi were only noted in the latter group (n=3; 5.7%). All thrombi resolved after low-molecular weight heparin treatment.

In contrast, in a prospective comparative study enrolling 80 patients two different devices (Watchman and Amplatzer Cardiac Plug; St Jude Medical) were compared as well as two different antithrombotic treatment strategies 12. While, the device seemed not to exert an influence on thrombus formation, the individual drug regimen clearly did: Patients with a six week course of dual platelet inhibition showed a significantly lower thrombus rate of 1.7% (1/59 patients) compared to 15.8% (3/19 patients) of patients on oral anticoagulation (p=0.042).

In conclusion, a post-implant drug regimen with dual platelet inhibition appears to be effective in preventing thrombus formation on the device but is still associated with a considerable rate of bleeding events. Moreover, the optimal duration of dual platelet inhibition treatment remains ill defined.

 

Open issues and future challenges

Since current atrial fibrillation guideline focuses its recommendation to interventional LAAC on patients with contraindications to long-term oral anticoagulation and usually high HASBLED scores the quest for alternative post-implant drug regimen is of particular importance. In addition to a randomised comparison of oral anticoagulation and dual platelet inhibition, the use of direct oral anticoagulants could be a viable alternative. Unfortunately, to date there are not published data on this drug group.

Finally, it would be desirable to obviate the need for a lifelong aspirin treatment. Most recent studies have shown the considerable bleeding rate on ASA in elderly and patients contraindicated to oral anticoagulation13. In the latter study, the event rate was as high as on the direct factor Xa inhibitor apixaban.

In order to collect real-life data, a post-market, multicentre, observational registry evaluating clinical outcomes in atrial fibrillation patients receiving LAAC with Watchman (EWOLUTION) is currently enrolling patients.

 

References

 

1. Camm J, et al. Eur Heart J. 2012;33:2719–47.

2. Holmes DR, et al. Lancet. 2009;374:534–42.

3. Reddy VY, et al. Circulation. 2011;123:417–24.

4. Holmes DR, et al. J Am Coll Cardiol. 2014;64:1–12.

5. Patel MR, et al. N Engl J Med. 2011;365:883–891.

6. Connolly SJ, et al. N Engl J Med. 2011;364:806–817.

7. Connolly SJ, et al. N Engl J Med. 2009;361:1139–1151.

8. Viles-Gonzalez JF, et al. J Am Coll Cardiol. 2012;59:923–9.

9. Block PC, et al. JACC Cardiovasc Interv. 2009;2:594–600.

10. Reddy VY, et al. J Am Coll Cardiol. 2013;61:2551–6.

11. Meincke F, et al. EuroIntervention. 2013;9:463–8.

12. Chun KRJ, et al. HeartRhythm. 2013;10:1792–9.

13. Mant J, et al. Lancet. 2007;370:493–503.

 

Boris Schmidt and KR Julian Chun are from Cardioangiologisches Centrum Bethanien, Frankfurt, Germany

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